Goodman and Gilman Manual of Pharmacology and Therapeutics

Section III
Modulation of Cardiovascular Function

chapter 31
Drug Therapy for Hypercholesterolemia and Dyslipidemia

Hyperlipidemia is a major cause of atherosclerosis and atherosclerosis-induced conditions, such as coronary heart disease (CHD), ischemic cerebrovascular disease, and peripheral vascular disease. These conditions cause morbidity or mortality in a majority of middle-aged or older adults. Dyslipidemias, including hyperlipidemia (hypercholesterolemia) and low levels of high-density-lipoprotein cholesterol (HDL-C), are major causes of increased atherogenic risk; both genetic disorders and lifestyle contribute to the dyslipidemias seen in countries around the world.

Classes of drugs that modify cholesterol levels include:

• Statins, inhibitors of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase

• Bile acid–binding resins

• Nicotinic acid (niacin)

• Fibric acid derivatives

• Ezetimibe, an inhibitor of cholesterol absorption

These drugs provide benefit in patients across the entire spectrum of cholesterol levels, primarily by reducing levels of low-density-lipoprotein cholesterol (LDL-C). Drug regimens that reduce LDL-C levels moderately (30-40%) can reduce fatal and nonfatal CHD events and strokes by as much as 30-40%. In patients with low HDL-C and average LDL-C levels, appropriate drug therapy reduces CHD endpoint events by 20-35%. Because two-thirds of patients with CHD in the U.S. have low HDL-C levels (<40 mg/dL in men, <50 mg/dL in women), low-HDL-C patients should be treated for dyslipidemia, even if their LDL-C levels are in the normal range.

Severe hypertriglyceridemia (i.e., triglyceride levels of >1000 mg/dL) requires therapy to prevent pancreatitis. Moderately elevated triglyceride levels (150-400 mg/dL) are of concern because they often occur as part of the metabolic syndrome, which includes insulin resistance, obesity, hypertension, low HDL-C levels, a procoagulant state, and substantially increased risk of CVD. Atherogenic dyslipidemia in patients with metabolic syndrome also is characterized by lipid-depleted LDL (sometimes referred to as “small, dense LDL”). Metabolic syndrome affects ~25% of adults and is common in CVD patients; hence, identification of moderate hypertriglyceridemia in a patient, even if the total cholesterol level is normal, should trigger an evaluation to identify insulin-resistant patients with this disorder.


Lipoproteins are macromolecular assemblies that contain lipids and proteins. The lipid constituents include free and esterified cholesterol, triglycerides, and phospholipids. The protein components, known as apolipoproteins or apoproteins, provide structural stability to the lipoproteins and also may function as ligands in lipoprotein–receptor interactions or as cofactors in enzymatic processes that regulate lipoprotein metabolism. The major classes of lipoproteins and their properties are summarized in Table 31–1. Apoproteins have well-defined roles in plasma lipoprotein metabolism (Table 31–2).

Table 31–1

Characteristics of Plasma Lipoproteins


Table 31–2



In all spherical lipoproteins, the most water-insoluble lipids (cholesteryl esters and triglycerides) are core components, and the more polar, water-soluble components (apoproteins, phospholipids, and unesterified cholesterol) are located on the surface. Except for apo(a), the lipid-binding regions of all apoproteins contain amphipathic helices that interact with the polar, hydrophilic lipids (such as surface phospholipids) and with the aqueous plasma environment in which the lipoproteins circulate. Differences in the non–lipid-binding regions determine the functional specificities of the apolipoproteins.

Figure 31–1 summarizes the pathways involved in the uptake and transport of dietary fat and cholesterol, pathways that involve the lipoprotein structures described below.


Figure 31–1 The major pathways involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by the liver. Chylomicrons are converted to chylomicron remnants by the hydrolysis of their triglycerides by LPL. Chylomicron remnants are rapidly cleared from the plasma by the liver. “Remnant receptors” include the LDL receptor–related protein (LRP), LDL receptors, and perhaps other receptors. Free fatty acid (FFA) released by LPL is used by muscle tissue as an energy source or taken up and stored by adipose tissue. HL, hepatic lipase; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins.

CHYLOMICRONS. Chylomicrons are synthesized from the fatty acids of dietary triglycerides and cholesterol absorbed by epithelial cells in the small intestine. Chylomicrons are the largest and lowest density plasma lipoproteins. In normolipidemic individuals, chylomicrons are present in plasma for 3-6 h after a fat-containing meal has been ingested. Intestinal cholesterol absorption is mediated by Niemann-Pick C1–Like 1 protein (NPC1L1), which appears to be the target of ezetimibe, a cholesterol absorption inhibitor.

After their synthesis in the endoplasmic reticulum, triglycerides are transferred by microsomal triglyceride transfer protein (MTP) to the site where newly synthesized apoB-48 is available to form chylomicrons. ApoB-48, synthesized only by intestinal epithelial cells, is unique to chylomicrons and functions primarily as a structural component of chylomicrons. Dietary cholesterol is esterified by the type 2 isozyme of acyl coenzyme A:cholesterol acyltransferase (ACAT-2). ACAT-2 is found in the intestine and in the liver, where cellular free cholesterol is esterified before triglyceride-rich lipoproteins (chylomicrons and very-low-density lipoproteins [VLDL]) are assembled.

After entering the circulation via the thoracic duct, chylomicrons are metabolized initially at the capillary luminal surface of tissues that synthesize lipoprotein lipase (LPL), (see Figure 31–1), including adipose tissue, skeletal and cardiac muscle, and breast tissue of lactating women. The resulting free fatty acids are taken up and used by the adjacent tissues. The interaction of chylomicrons and LPL requires apoC-II as a cofactor.

CHYLOMICRON REMNANTS. After LPL-mediated removal of much of the dietary triglycerides, the chylomicron remnants, with all of the dietary cholesterol, detach from the capillary surface and within minutes are removed from the circulation by the liver (see Figure 31–1). First, the remnants are sequestered by the interaction of apoE with heparan sulfate proteoglycans on the surface of hepatocytes and are processed by hepatic lipase (HL), further reducing the remnant triglyceride content. Next, apoE mediates remnant uptake by interacting with the hepatic LDL receptor or the LDL receptor–related protein (LRP).

During the initial hydrolysis of chylomicron triglycerides by LPL, apoA-I and phospholipids are shed from the surface of chylomicrons and remain in the plasma. This is one mechanism by which nascent (precursor) HDL are generated. Chylomicron remnants are not precursors of LDL, but the dietary cholesterol delivered to the liver by remnants increases plasma LDL levels by reducing LDL receptor–mediated catabolism of LDL by the liver.

VERY-LOW-DENSITY LIPOPROTEINS. VLDL are produced in the liver when triglyceride production is stimulated by an increased flux of free fatty acids or by increased de novo synthesis of fatty acids by the liver.

ApoB-100, apoE, and apoC-I, C-II, and C-III are synthesized constitutively by the liver and incorporated into VLDL (see Table 31–2). Triglycerides are synthesized in the endoplasmic reticulum, and along with other lipid constituents, are transferred by MTP to the site in the endoplasmic reticulum where newly synthesized apoB-100 is available to form nascent (precursor) VLDL. Small amounts of apoE and the C apoproteins are incorporated into nascent particles within the liver before secretion, but most of these apoproteins are acquired from plasma HDL after the VLDL are secreted by the liver. Mutations of MTP that result in the inability of triglycerides to be transferred to either apoB-100 in the liver or apoB-48 in the intestine prevent VLDL and chylomicron production and cause the genetic disorderabetalipoproteinemia.

Plasma VLDL is catabolized by LPL in the capillary beds in a process similar to the lipolytic processing of chylomicrons (see Figure 31–1). When triglyceride hydrolysis is nearly complete, the VLDL remnants, usually termed IDL, are released from the capillary endothelium and reenter the circulation. ApoB-100 containing small VLDL and IDL, which have a t1/2 <30 min, have 2 potential fates. About 40-60% are cleared from the plasma by the liver via apoB-100 and apoE-mediated interaction with LDL receptors and LRP. LPL and HL convert the remainder of the IDL to LDL by removal of additional triglycerides. The C apoproteins, apoE, and apoA-V redistribute to HDL.

ApoE plays a major role in the metabolism of triglyceride-rich lipoproteins (chylomicrons, chylomicron remnants, VLDL, and IDL). About half of the apoE in the plasma of fasting subjects is associated with triglyceride-rich lipoproteins, and the other half is a constituent of HDL.

LOW-DENSITY LIPOPROTEINS. Virtually all of the LDL particles in the circulation are derived from VLDL. The LDL particles have a t1/2 of 1.5-2 days. In subjects without hypertriglyceridemia, two-thirds of plasma cholesterol is found in the LDL. Plasma clearance of LDL is mediated primarily by LDL receptors (ApoB-100 binds LDL to its receptor); a small component is mediated by nonreceptor clearance mechanisms.

The most common cause of autosomal dominant hypercholesterolemia involves mutations of the LDL receptor gene. Defective or absent LDL receptors cause high levels of plasma LDL and familial hypercholesterolemia. LDL becomes atherogenic when modified by oxidation, a required step for LDL uptake by the scavenger receptors of macrophages. This process leads to foam-cell formation in arterial lesions. At least 2 scavenger receptors (SRs) are involved (SR-AI/II and CD36). SR-AI/II appears to be expressed more in early atherogenesis, and CD36 expression is greater as foam cells form during lesion progression. The liver expresses a large complement of LDL receptors and removes ~75% of all LDL from the plasma. Consequently, manipulation of hepatic LDL receptor gene expression is a most effective way to modulate plasma LDL-C levels. Thyroxine and estrogen enhance LDL receptor gene expression, which explains their LDL-C–lowering effects. The most effective dietary alteration (decreased consumption of saturated fat and cholesterol) and pharmacological treatment (statins) for hypercholesterolemia act by enhancing hepatic LDL receptor expression.

HIGH-DENSITY LIPOPROTEINS. HDL are protective lipoproteins that decrease the risk of CHD; thus, high levels of HDL are desirable. This protective effect may result from the participation of HDL in reverse cholesterol transport, the process by which excess cholesterol is acquired from cells and transferred to the liver for excretion. HDL effects also include putative anti-inflammatory, anti-oxidative, platelet anti-aggregatory, anticoagulant, and profibrinolytic activities. ApoA-I is the major HDL apoprotein, and its plasma concentration is a more powerful inverse predictor of CHD risk than is the HDL-C level. ApoA-I synthesis is required for normal production of HDL.

Mutations in the apoA-I gene that cause HDL deficiency often are associated with accelerated atherogenesis. In addition, 2 major subclasses of mature HDL particles in the plasma can be differentiated by their content of the major HDL apoproteins, apoA-I and apoA-II. Epidemiologic evidence in humans suggests that apoA-II may be atheroprotective.

The membrane transporter ABCA1 facilitates the transfer of free cholesterol from cells to HDL. After free cholesterol is acquired by the pre-β1 HDL, it is esterified by lecithin:cholesterol acyltransferase. The newly esterified and nonpolar cholesterol moves into the core of the particle, which becomes progressively more spherical, larger, and less dense with continued cholesterol acquisition and esterification. As the cholesteryl ester content of the particle (now called HDL2) increases, the cholesteryl esters of these particles begin to be exchanged for triglycerides derived from any of the triglyceride-containing lipoproteins (chylomicrons, VLDL, remnant lipoproteins, and LDL). This exchange, mediated by the cholesteryl ester transfer protein (CETP), accounts for the removal of about two-thirds of the cholesterol associated with HDL in humans. The transferred cholesterol subsequently is metabolized as part of the lipoprotein into which it was transferred.

Treatments that target CETP and the ABC transporters have yielded equivocal results in humans. While CETP inhibitors effectively reduce LDL, they also paradoxically increase the frequency of adverse cardiovascular events (angina, revascularization, myocardial infarction, heart failure, and death).

The triglyceride that is transferred into HDL2 is hydrolyzed in the liver by HL, a process that regenerates smaller, spherical HDL3 particles that recirculate and acquire additional free cholesterol from tissues containing excess free cholesterol.

HL activity is regulated and modulates HDL-C levels. Androgens increase HL gene expression/activity, which accounts for the lower HDL-C values observed in men than in women. Estrogens reduce HL activity, but their impact on HDL-C levels in women is substantially less than that of androgens on HDL-C levels in men. HL appears to have a pivotal role in regulating HDL-C levels, as HL activity is increased in many patients with low HDL-C levels.

LIPOPROTEIN (a). Lipoprotein(a) [Lp(a)] is composed of an LDL particle that has a second apoprotein, apo(a), in addition to apoB-100. Apo(a) of Lp(a) is structurally related to plasminogen and appears to be atherogenic.


The major conventional risk factors for CVD are elevated LDL-C, reduced HDL-C, cigarette smoking, hypertension, type 2 diabetes mellitus, advancing age, and a family history of premature CHD events (men <55 years; women <65 years) in a first-degree relative (Table 31–3). When total cholesterol levels are below 160 mg/dL, CHD risk is markedly attenuated, even in the presence of additional risk factors. This pivotal role of hypercholesterolemia in atherogenesis gave rise to the almost universally accepted cholesterol-diet-CHD hypothesis: elevated plasma cholesterol levels cause CHD, diets rich in saturated (animal) fat and cholesterol raise cholesterol levels, and lowering cholesterol levels reduces CHD risk.

Table 31–3

Risk Factors for Coronary Heart Disease


Modest reductions in total cholesterol and LDL-C are associated with reductions in fatal and nonfatal CHD events but not total mortality. Patients benefit regardless of gender, age, baseline lipid values, or whether they have a prior history of vascular disease or type 2 diabetes mellitus. Statin therapy is effective in preventing first and subsequent atherothrombotic strokes. Moderate doses of statins that lower LDL-C levels by about 40% reduce cardiovascular events by about one-third. More intensive regimens that lower LDL-C by 45-50% reduce CVD events by as much as 50%.


Primary prevention involves management of risk factors to prevent a first-ever CHD event. Secondary prevention is aimed at patients who have had a prior CHD event and whose risk factors must be treated aggressively. Recently, the concept of primordial prevention has been applied to CHD. This is a population-based approach to prevention (rather than treatment) that targets smoking, weight management, physical activity, healthy eating habits, cholesterol and glucose levels, and blood pressure.

The patient-based approach to manage dyslipidemia is designed for primary and secondary prevention, requires a risk assessment, and focuses on lowering LDL-C and non-HDL-C (see ranges in Table 31–4). Before drug therapy is initiated, secondary causes of hyperlipidemia (Table 31–5) should be excluded. Treatment of the disorder causing secondary dyslipidemia may preclude the necessity of treatment with hypolipidemic drugs. Table 31–6 summarizes current risk category-treatment guidelines based on LDL-C levels.

Table 31–4

Classification of Plasma Lipid Levels (mg/dL)


Table 31–5

Secondary Causes of Dyslipidemia


Table 31–6

Treatment Based on LDL-C Levels(2004 Revision of NCEP Adult Treatment Panel III Guidelines)



Large-scale trials with statins have provided new insights into which patients with dyslipidemia should be treated and when treatment should be initiated.

Gender. Both men and women benefit from lipid-lowering therapy. Statins are the recommended first-line drug therapy for lowering lipids and preventing CHD events in postmenopausal women.

Age. Age >45 years in men and >55 years in women is considered to be a CHD risk factor. The statin trials have shown that patients >65 years of age benefit from therapy as much as do younger patients. Old age per se is not a reason to refrain from initiating drug therapy in an otherwise healthy person.

Cerebrovascular Disease Patients. Plasma cholesterol levels correlate positively with the risk of ischemic stroke and statins reduce stroke and transient ischemic attacks in patients with and without CHD.

Peripheral Vascular Disease Patients. Statins are beneficial in patients with peripheral vascular disease.

Hypertensive Patients and Smokers. The risk reduction for coronary events in statin trials of hypertensive patients and smokers is similar to that in subjects without hypertension.

Type 2 Diabetes Mellitus. Patients with type 2 diabetes benefit very significantly from aggressive lipid lowering (see below).

Post–Myocardial Infarction or Revascularization Patients. As soon as CHD is diagnosed, it is essential to begin lipid-lowering therapy (NCEP guidelines: LDL-C goal <70 mg/dL for very high-risk patients). Statin therapy also improves the long-term outcome after bypass surgery.


Diabetes mellitus is an independent predictor of high risk for CHD. Glucose control is essential but provides only minimal benefit with respect to CHD prevention. Aggressive treatment of diabetic dyslipidemia through diet, weight control, and drugs is critical in reducing risk. Diabetic dyslipidemia usually is characterized by high triglycerides, low HDL-C, and moderate elevations of total cholesterol and LDL-C. Diabetics without diagnosed CHD have the same level of risk as nondiabetics with established CHD. Thus, the dyslipidemia treatment guidelines for diabetic patients are the same as for patients with CHD, irrespective of whether the diabetic patient has had a CHD event.


There is an increased CHD risk associated with the insulin-resistant, prediabetic state described under the rubric of “metabolic syndrome.” This syndrome consists of a constellation of 5 CHD risk factors: abdominal obesity, hypertension, insulin-resistance, hypertriglyceridemia, and low HDL (Table 31–7). Treatment should focus on weight loss and increased physical activity. Specific treatment of lipid abnormalities should also be undertaken.

Table 31–7

Clinical Identification of the Metabolic Syndrome



There is increased CHD risk associated with the presence of triglyceride levels >150 mg/dL. Three categories of hypertriglyceridemia are recognized (see Table 31–4), and treatment is recommended based on the degree of elevation. Weight loss, increased exercise, and alcohol restriction are important for all hypertriglyceridemic patients. If triglycerides remain >200 mg/dL after the LDL-C goal is reached (see Table 31–6), further reduction in triglycerides may be achieved by increasing the dose of a statin or of niacin. Combination therapy (statin plus niacin or statin plus fibrate) may be required, but caution is necessary with these combinations to avoid myopathy (see below).


The most frequent risk factor for premature CHD is low HDL-C.

In patients with low HDL-C, the total cholesterol:HDL-C ratio is a particularly useful predictor of CHD risk. Observational studies suggest that a ratio >4.5 is associated with increased risk (Table 31–8). The treatment of low HDL-C patients focuses on lowering LDL-C to the target level based on the patient’s risk factor or CHD status (see Table 31–6and a reduction of VLDL cholesterol to <30 mg/dL to reach the target for non-HDL-C. Satisfactory treatment results are a ratio of total cholesterol: HDL-C ≤3.5.

Table 31–8

Guidelines Based on LDL-C and Total Cholesterol:HDL-C Ratio for Treatment of Low HDL-C Patientsa




The statins are the most effective and best-tolerated agents for treating dyslipidemia. These drugs are competitive inhibitors of HMG-CoA reductase, which catalyzes an early, rate-limiting step in cholesterol biosynthesis. Higher doses of the more potent statins (e.g., atorvastatin, simvastatin, and rosuvastatin) also can reduce triglyceride levels caused by elevated VLDL levels. Some statins also are indicated for raising HDL-C levels, although the clinical significance of these effects on HDL-C remains to be proven. Figure 31–2 shows a representative statin structure and the reaction catalyzed by HMG-CoA reductase.


Figure 31–2 Lovastatin and HMG-CoA reductase reaction.


Statins exert their major effect—reduction of LDL levels—through a mevalonic acid–like moiety that competitively inhibits HMG-CoA reductase. By reducing the conversion of HMG-CoA to mevalonate, statins inhibit an early and rate-limiting step in cholesterol biosynthesis. Statins affect blood cholesterol levels by inhibiting hepatic cholesterol synthesis, which results in increased expression of the LDL receptor gene. Some studies suggest that statins also can reduce LDL levels by enhancing the removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL production. The reduction in hepatic VLDL production induced by statins is thought to be mediated by reduced synthesis of cholesterol, a required component of VLDL.


Triglyceride Reduction by Statins. Triglyceride levels >250 mg/dL are reduced substantially by statins, and the percent reduction achieved is similar to the percent reduction in LDL-C.

Effect of Statins on HDL-C Levels. Most studies of patients treated with statins have systematically excluded patients with low HDL-C levels. In studies of patients with elevated LDL-C levels and gender-appropriate HDL-C levels (40-50 mg/dL for men; 50-60 mg/dL for women), an increase in HDL-C of 5-10% was observed, irrespective of the dose or statin employed. However, in patients with reduced HDL-C levels (<35 mg/dL), statins may differ in their effects on HDL-C levels. More studies are needed to ascertain whether the effects of statins on HDL-C in patients with low HDL-C levels are clinically significant.

Effects of Statins on LDL-C Levels. Dose-response relationships for all statins demonstrate that the efficacy of LDL-C lowering is log-linear; LDL-C is reduced by ~6% (from baseline) with each doubling of the dose. Maximal effects on plasma cholesterol levels are achieved within 7-10 days. The statins are effective in almost all patients with high LDL-C levels. The exception is patients with homozygous familial hypercholesterolemia, who have very attenuated responses to the usual doses of statins because both alleles of the LDL receptor gene code for dysfunctional LDL receptors. Statin therapy does not reduce Lp(a) levels.

Potential Cardioprotective Effects Other Than LDL Lowering. Although the statins clearly exert their major effects on CHD by lowering LDL-C and improving the lipid profile as reflected in plasma cholesterol levels, a multitude of potentially cardioprotective effects are being ascribed to these drugs. However, it is not known whether these potential pleiotropic effects represent a class-action effect, differ among statins, or are biologically or clinically relevant.


After oral administration, intestinal absorption of the statins is variable (30-85%). All the statins, except simvastatin and lovastatin, are administered in the β-hydroxy acid form, which is the form that inhibits HMG-CoA reductase. Simvastatin and lovastatin are administered as inactive lactones that must be transformed in the liver to their respective β-hydroxy acids, simvastatin acid (SVA) and lovastatin acid (LVA). There is extensive first-pass hepatic uptake of all statins, mediated primarily by the organic anion transporter OATP1B1 (see Chapter 5).

Due to extensive first-pass hepatic uptake, systemic bioavailability of the statins and their hepatic metabolites varies between 5% and 30% of administered doses. The metabolites of all statins, except fluvastatin and pravastatin, have some HMG-CoA reductase inhibitory activity. Under steady-state conditions, small amounts of the parent drug and its metabolites produced in the liver can be found in the systemic circulation. In the plasma, >95% of statins and their metabolites are protein bound, with the exception of pravastatin and its metabolites, which are only 50% bound. Peak plasma concentrations of statins are achieved in 1-4 h. The t1/2 of the parent compounds are 1-4 h, except in the case of atorvastatin and rosuvastatin, which have half-lives of ~20 h, and simvastatin with a t1/2 ~12 h. The longer t1/2of atorvastatin and rosuvastatin may contribute to their greater cholesterol-lowering efficacy. The liver biotransforms all statins, and more than 70% of statin metabolites are excreted by the liver, with subsequent elimination in the feces.


Hepatotoxicity. Although serious hepatotoxicity is rare, a rate of about 1 case per million person-years of use; it is reasonable to measure alanine aminotransferase (ALT) at baseline and thereafter when clinically indicated.

Myopathy. The major adverse effect associated with statin use is myopathy. The risk of myopathy and rhabdomyolysis increases in proportion to statin dose and plasma concentrations. Consequently, factors inhibiting statin catabolism are associated with increased myopathy risk, including advanced age (especially >80 years of age), hepatic or renal dysfunction, perioperative periods, multisystem disease (especially in association with diabetes mellitus), small body size, and untreated hypothyroidism. Concomitant use of drugs that diminish statin catabolism or interfere with hepatic uptake is associated with myopathy and rhabdomyolysis in 50-60% of all cases. The most common statin interactions occurred with fibrates, especially gemfibrozil (38%), cyclosporine (4%), digoxin (5%), warfarin (4%), macrolide antibiotics (3%), mibefradil (2%), and azole antifungals (1%). Other drugs that increase the risk of statin-induced myopathy include niacin (rare), HIV protease inhibitors, amiodarone, and nefazodone.

Gemfibrozil, the drug most commonly associated with statin-induced myopathy, inhibits both uptake of the active hydroxy acid forms of statins into hepatocytes by OATP1B1 and interferes with the transformation of most statins by glucuronidases. Coadministration of gemfibrozil nearly doubles the plasma concentration of the statin hydroxy acids. When statins are administered with niacin, the myopathy probably is caused by an enhanced inhibition of skeletal muscle cholesterol synthesis (a pharmacodynamic interaction).

Drugs that interfere with statin oxidation are those metabolized primarily by CYP3A4 and include certain macrolide antibiotics (e.g., erythromycin); azole antifungals (e.g., itraconazole); cyclosporine; nefazodone, a phenylpiperazine antidepressant; HIV protease inhibitors; and amiodarone. These pharmacokinetic interactions are associated with increased plasma concentrations of statins and their active metabolites. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYPs 3A4 and 3A5. Fluvastatin is mostly (50-80%) metabolized by CYP2C9 to inactive metabolites, but CYP3A4 and CYP2C8 also contribute to its metabolism. Pravastatin, however, is not metabolized to any appreciable extent by the CYP system and is excreted unchanged in the urine. Because pravastatin, fluvastatin, and rosuvastatin are not extensively metabolized by CYP3A4, these statins may be less likely to cause myopathy when used with one of the predisposing drugs. However, the benefits of combined therapy with any statin should be carefully weighed against the risk of myopathy.

THERAPEUTIC USES. Hepatic cholesterol synthesis is maximal between midnight and 2:00 A.M. Thus, statins with t1/2 ≤4 h (all but atorvastatin and rosuvastatin) should be taken in the evening. Each statin has a low recommended starting dose that reduces LDL-C by 20-30% (Table 31–9).

Table 31–9

Statin Doses (mg) Required for Reductions in LDL-C


The initial recommended dose of lovastatin (MEVACOR) is 20 mg and is slightly more effective if taken with the evening meal than if it is taken at bedtime. The dose of lovastatin may be increased every 3-6 weeks up to a maximum of 80 mg/day. The 80-mg dose is slightly (2-3%) more effective if given as 40 mg twice daily. Lovastatin, at 20 mg, is marketed in combination with 500, 750, or 1000 mg of extended-release niacin (ADVICOR). Few patients are appropriate candidates for this fixed-dose combination (see next section on “Nicotinic Acid”).

The usual starting dose of simvastatin (ZOCOR) for most patients is 20 mg at bedtime. The maximal dose is 80 mg. In patients taking cyclosporine, fibrates, or niacin, the daily dose should not exceed 20 mg. Simvastatin, 20 mg, is marketed in combination with 500, 750, or 1000 mg of extended-release niacin (SIMCOR).

Pravastatin (PRAVACHOL) therapy is initiated with a 20- or 40-mg dose that may be increased to 80 mg. This drug should be taken at bedtime. Because pravastatin is a hydroxy acid, bile-acid sequestrants will bind it and reduce its absorption. Pravastatin also is marketed in combination with buffered aspirin (PRAVIGARD). The small advantage of combining these 2 drugs should be weighed against the disadvantages inherent in fixed-dose combinations.

For fluvastatin (LESCOL), the starting dose is 20 or 40 mg, and the maximum is 80 mg/day. Like pravastatin, it is administered as a hydroxy acid and should be taken at bedtime, several hours after ingesting a bile-acid sequestrant (if the combination is used).

Atorvastatin (LIPITOR) has a long t1/2, which allows administration of this statin at any time of the day. The starting dose is 10 mg, and the maximum is 80 mg/day. Atorvastatin is marketed in combination with the Ca2+-channel blocker amlodipine (CADUET) for patients with hypertension or angina as well as hypercholesterolemia.

Rosuvastatin (CRESTOR) is available in doses ranging between 5 and 40 mg. It has a t1/2 of 20-30 h and may be taken at any time of day. If the combination of gemfibrozil with rosuvastatin is used, the dose of rosuvastatin should not exceed 10 mg.

Pitavastatin (LIVALO) is available in doses of 1, 2, and 4 mg. Gemfibrozil reduces clearance of pitavastatin and raises blood concentrations; consequently, gemfibrozil should be used cautiously, if at all, in combination with pitavastatin.

The choice of statins should be based on efficacy (reduction of LDL-C) and cost. Three drugs (lovastatin, simvastatin, and pravastatin) have been used safely in clinical trials. Baseline determinations of ALT and repeat testing at 3-6 months are recommended. If ALT is normal after the initial 3-6 months, then it need not be repeated more than once every 6-12 months. Measurements of CK are not routinely necessary unless the patient also is taking a drug that enhances the risk of myopathy.

Statins in Combination with Other Lipid-Lowering Drugs. Statins, in combination with the bile acid–binding resins cholestyramine and colestipol, produce 20-30% greater reductions in LDL-C than can be achieved with statins alone. Preliminary data indicate that colesevelam hydrochloride plus a statin lowers LDL-C by 8-16% more than statins alone. Niacin also can enhance the effect of statins, but the occurrence of myopathy increases when statin doses >25% of maximum (e.g., 20 mg of simvastatin or atorvastatin) are used with niacin. The combination of a fibrate (clofibrate, gemfibrozil, or fenofibrate) with a statin is particularly useful in patients with hypertriglyceridemia and high LDL-C levels. This combination increases the risk of myopathy but usually is safe with a fibrate at its usual maximal dose and a statin at no more than 25% of its maximal dose. Triple therapy with resins, niacin, and statins can reduce LDL-C by up to 70%. VYTORIN, a fixed-dose combination of simvastatin (10, 20, 40, or 80 mg) and ezetimibe (10 mg), decreased LDL-C levels by up to 60% at 24 weeks.

Statin Use by Children. Some statins have been approved for use in children with heterozygous familial hypercholesterolemia. Atorvastatin, lovastatin, and simvastatin are indicated for children >11 years. Pravastatin is approved for children ≤8 years.

Pregnancy. The safety of statins during pregnancy has not been established.


CHOLESTYRAMINE, COLESTIPOL, COLESEVELAM. The bile-acid sequestrants cholestyramine and colestipol are among the oldest of the hypolipidemic drugs and are probably the safest, because they are not absorbed from the intestine. These resins also are recommended for patients 11-20 years of age. Because statins are so effective as monotherapy, the resins are most often used as second agents if statin therapy does not lower LDL-C levels sufficiently. When used with a statin, cholestyramine and colestipol usually are prescribed at submaximal doses. Maximal doses can reduce LDL-C by up to 25% but are associated with unacceptable GI side effects (bloating and constipation). Colesevelam, a newer bile-acid sequestrant, lowers LDL-C by 18% at its maximum dose.

MECHANISM OF ACTION. The bile-acid sequestrants are highly positively charged and bind negatively charged bile acids. Because of their large size, the resins are not absorbed, and the bound bile acids are excreted in the stool. Because more than 95% of bile acids are normally reabsorbed, interruption of this process depletes the pool of bile acids, and hepatic bile-acid synthesis increases. As a result, hepatic cholesterol content declines, stimulating the production of LDL receptors, an effect similar to that of statins. The increase in hepatic LDL receptors increases LDL clearance and lowers LDL-C levels, but this effect is partially offset by the enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase. Inhibition of reductase activity by a statin substantially increases the effectiveness of the resins. The resin-induced increase in bile-acid production is accompanied by an increase in hepatic triglyceride synthesis, which is of consequence in patients with significant hypertriglyceridemia (baseline triglyceride level >250 mg/dL). Use of colesevelam to lower LDL-C levels in hypertriglyceridemic patients should be accompanied by frequent (every 1-2 weeks) monitoring of fasting triglyceride levels.

EFFECTS ON LIPOPROTEIN LEVELS. The reduction in LDL-C by resins is dose dependent. Doses of 8-12 g of cholestyramine or 10-15 g of colestipol are associated with 12-18% reductions in LDL-C. Maximal doses (24 g of cholestyramine, 30 g of colestipol) may reduce LDL-C by as much as 25% but will cause GI side effects. One to 2 weeks is sufficient to attain maximal LDL-C reduction by a given resin dose. In patients with normal triglyceride levels, triglycerides may increase transiently and then return to baseline. HDL-C levels increase 4-5%. Statins plus resins or niacin plus resins can reduce LDL-C by 40-60%. Colesevelam, in doses of 3-3.75 g, reduces LDL-C levels by 9-19%.

ADVERSE EFFECTS AND DRUG INTERACTIONS. The resins are generally safe, as they are not systemically absorbed. Because they are administered as chloride salts, rare instances of hyperchloremic acidosis have been reported. Severe hypertriglyceridemia is a contraindication to the use of cholestyramine and colestipol because these resins increase triglyceride levels. At present, there are insufficient data on the effect of colesevelam on triglyceride levels.

Cholestyramine and colestipol both are available as a powder that must be mixed with water and drunk as a slurry. The gritty sensation is unpleasant but generally tolerated. Colestipol is available in a tablet form. Colesevelam is available as a hard capsule that absorbs water and creates a soft, gelatinous material that allegedly minimizes the potential for GI irritation. Patients taking cholestyramine and colestipol complain of bloating and dyspepsia. These symptoms can be substantially reduced if the drug is completely suspended in liquid several hours before ingestion. Constipation may occur but sometimes can be prevented by adequate daily water intake and psyllium. Colesevelam may be less likely to cause the dyspepsia, bloating, and constipation.

Cholestyramine and colestipol bind and interfere with the absorption of many drugs, including some thiazides, furosemide, propranolol, L-thyroxine, digoxin, warfarin, and some of the statins. The effect of cholestyramine and colestipol on the absorption of most drugs has not been studied. For this reason, it is wise to administer all drugs either 1 h before or 3-4 h after a dose of cholestyramine or colestipol. Colesevelam does not appear to interfere with the absorption of fat-soluble vitamins or of drugs such as digoxin, lovastatin, warfarin, metoprolol, quinidine, and valproic acid. Colesevelam reduces the maximum concentration and the AUC of sustained-release verapamil by 31% and 11%, respectively. In the absence of information to the contrary, prudence suggests that patients take other medications 1 h before or 3-4 h after a dose of colesevelam. The safety and efficacy of colesevelam have not been studied in pediatric patients or pregnant women.

PREPARATIONS AND USE. The powdered forms of cholestyramine (QUESTRAN, others, 4 g/dose) and colestipol (COLESTID, others, 5 g/dose) are either mixed with a fluid (water or juice) and drunk as a slurry or mixed with crushed ice in a blender. Ideally, patients should take the resins before breakfast and before supper, starting with 1 scoop or packet twice daily, and increasing the dosage after several weeks or longer as needed and as tolerated. Patients generally will not take more than 2 doses (scoops or packets) twice daily. Colesevelam hydrochloride (WELCHOL) is available as a solid tablet containing 0.625 g of colesevelam and as a powder in packets of 3.75 g or 1.875 g. The starting dose is either 3 tablets taken twice daily with meals or all 6 tablets taken with a meal. The tablets should be taken with a liquid. The maximum daily dose is 7 tablets (4.375 g).


Niacin is a water-soluble B-complex vitamin that functions as a vitamin only after conversion to NAD or NADP, in which it occurs as an amide. Both niacin and its amide may be given orally as a source of niacin for its functions as a vitamin, but only niacin affects lipid levels. The hypolipidemic effects of niacin require larger doses than are required for its vitamin effects.


MECHANISM OF ACTION. In adipose tissue, niacin inhibits the lipolysis of triglycerides by hormone-sensitive lipase, which reduces transport of free fatty acids to the liver and decreases hepatic triglyceride synthesis. Niacin may exert its effects on lipolysis by stimulating a GPCR (GPR109A) that couples to Gi and inhibits cyclic AMP production in adipocytes. In the liver, niacin reduces triglyceride synthesis by inhibiting both the synthesis and esterification of fatty acids, effects that increase apoB degradation. Reduction of triglyceride synthesis reduces hepatic VLDL production, which accounts for the reduced LDL levels. Niacin also enhances LPL activity, which promotes the clearance of chylomicrons and VLDL triglycerides. Niacin raises HDL-C levels by decreasing the fractional clearance of apoA-I in HDL rather than by enhancing HDL synthesis.

EFFECTS ON PLASMA LIPOPROTEIN LEVELS. Regular or crystalline niacin in doses of 2-6 g/day reduces triglycerides by 35-50% (as effectively as fibrates and statins); the maximal effect occurs within 4-7 days. Reductions of 25% in LDL-C levels are possible with doses of 4.5-6 g/day; 3-6 weeks are required for maximal effect. Niacin is the best agent available for increasing HDL-C (30-40%), but the effect is less in patients with HDL-C levels >35 mg/dL. Niacin also is the only lipid-lowering drug that reduces Lp(a) levels significantly. Despite salutary effect on lipids, niacin’s side effects limit its use (see “Adverse Effects”).

ADME. The doses of regular (crystalline) niacin used to treat dyslipidemia are almost completely absorbed, and peak plasma concentrations (up to 0.24 mmol) are achieved within 30-60 min. The t1/2 is about 60 min, which necessitates dosing 2 to 3 times daily. At lower doses, most niacin is taken up by the liver; only the major metabolite, nicotinuric acid, is found in the urine. At higher doses, a greater proportion of the drug is excreted in the urine as unchanged nicotinic acid.

ADVERSE EFFECTS. Two of niacin’s side effects, flushing and dyspepsia, limit patient compliance. The cutaneous effects include flushing and pruritus of the face and upper trunk, skin rashes, and acanthosis nigricans. Flushing and associated pruritus are prostaglandin mediated. Taking an aspirin each day alleviates the flushing in many patients. Flushing is worse when therapy is initiated or the dosage is increased but ceases in most patients after 1-2 weeks of a stable dose. Flushing is more likely to occur when niacin is consumed with hot beverages or with alcohol. Flushing is minimized if therapy is initiated with low doses (100-250 mg twice daily) and if the drug is taken after a meal. Dry skin, a frequent complaint, can be dealt with by using skin moisturizers, and acanthosis nigricans can be dealt with by using lotions containing salicylic acid. Dyspepsia and rarer episodes of nausea, vomiting, and diarrhea are less likely to occur if the drug is taken after a meal. Patients with any history of peptic ulcer disease should not take niacin.

The most common, medically serious side effects are hepatotoxicity, manifested as elevated serum transaminases, and hyperglycemia. Both regular (crystalline) niacin and sustained-release niacin, which was developed to reduce flushing and itching, have been reported to cause severe liver toxicity. An extended-release niacin (NIASPAN) appears to be less likely to cause severe hepatotoxicity, perhaps simply because it is administered once daily. The incidence of flushing and pruritus with this preparation is not substantially different from that with regular niacin. Severe hepatotoxicity is more likely to occur when patients take more than 2 g of sustained-release, over-the-counter preparations. Affected patients experience flu-like fatigue and weakness. Usually, aspartate transaminase and ALT are elevated, serum albumin levels decline, and total cholesterol and LDL-C levels decline substantially.

In patients with diabetes mellitus, niacin should be used cautiously because niacin-induced insulin resistance can cause severe hyperglycemia. If niacin is prescribed for patients with known or suspected diabetes, blood glucose levels should be monitored at least weekly until proven to be stable. Niacin also elevates uric acid levels and may reactivate gout. A history of gout is a relative contraindication for niacin use. Rarer reversible side effects include toxic amblyopia and toxic maculopathy. Atrial tachyarrhythmias and atrial fibrillation have been reported, more commonly in elderly patients. Niacin, at doses used in humans, has been associated with birth defects in experimental animals and should not be taken by pregnant women.

THERAPEUTIC USE. Niacin is indicated for hypertriglyceridemia and elevated LDL-C; it is especially useful in patients with both hypertriglyceridemia and low HDL-C levels. There are 2 commonly available forms of niacin. Crystalline niacin (immediate-release or regular) refers to niacin tablets that dissolve quickly after ingestion. Sustained-release niacin refers to preparations that continuously release niacin for 6-8 h after ingestion. NIASPAN is the only preparation of niacin that is FDA-approved for treating dyslipidemia and that requires a prescription.

Crystalline niacin tablets are available over the counter in a variety of strengths from 50- to 500-mg tablets. The dose may be increased stepwise every 7 days to a total daily dose of 1.5-2 g. After 2-4 weeks at this dose, transaminases, serum albumin, fasting glucose, and uric acid levels should be measured. Lipid levels should be checked and the dose increased further until the desired effect on plasma lipids is achieved. After a stable dose is attained, blood should be drawn every 3-6 months to monitor for the various toxicities. Over-the-counter, sustained-release niacin preparations and NIASPAN are effective up to a total daily dose of 2 g. All doses of sustained-release niacin, but particularly doses above 2 g/day, have been reported to cause hepatotoxicity, which may occur soon after beginning therapy or after several years of use. The potential for severe liver damage should preclude use of OTC preparations in most patients. NIASPAN may be less likely to cause hepatotoxicity.

Because concurrent use of niacin and a statin can cause myopathy, the statin should be administered at no more than 25% of its maximal dose. Patients also should be instructed to discontinue therapy if flu-like muscle aches occur. Routine measurement of CK in patients taking niacin and statins does not assure that severe myopathy will be detected before onset of symptoms.


Clofibrate is a halogenated fibric acid derivative. Gemfibrozil is a nonhalogenated acid that is distinct from the halogenated fibrates. A number of fibric acid analogs (e.g., fenofibrate,bezafibrate, ciprofibrate) have been developed and are used in Europe and elsewhere.

MECHANISM OF ACTION. The mechanisms by which fibrates lower lipoprotein levels, or raise HDL levels, remain unclear. Many of the effects of these compounds on blood lipids are mediated by their interaction with peroxisome proliferator-activated receptors (PPARs), which regulate gene transcription. Fibrates bind to PPARα and reduce triglycerides through PPARα-mediated stimulation of fatty acid oxidation, increased LPL synthesis, and reduced expression of apoC-III. Increased LPL synthesis would enhance the clearance of triglyceride-rich lipoproteins. Reduced hepatic production of apoC-III, which serves as an inhibitor of lipolysis and receptor-mediated clearance, would enhance the clearance of VLDL. Fibrate-mediated increases in HDL-C are due to PPARV stimulation of apoA-I and apoA-II expression, which increases HDL levels. Fenofibrate is more effective than gemfibrozil at increasing HDL levels. Most fibrates have potential anti-thrombotic effects, including inhibition of coagulation and enhancement of fibrinolysis.

EFFECTS ON LIPOPROTEIN LEVELS. Effects of fibric acid agents on lipoprotein levels differ widely, depending on the starting lipoprotein profile, the presence or absence of a genetic hyperlipoproteinemia, the associated environmental influences, and the specific fibrate used. Patients with type III hyperlipoproteinemia (dysbetalipoproteinemia) are among the most sensitive responders to fibrates. Elevated triglyceride and cholesterol levels are dramatically lowered, and tuberoeruptive and palmar xanthomas may regress completely. Angina and intermittent claudication also improve.

In patients with mild hypertriglyceridemia (e.g., triglycerides <400 mg/dL), fibrate treatment decreases triglyceride levels by up to 50% and increases HDL-C concentrations by about 15%; LDL-C levels may be unchanged or increase. Normotriglyceridemic patients with heterozygous familial hypercholesterolemia usually experience little change in LDL levels with gemfibrozil; with the other fibric acid agents, reductions as great as 20% may occur in some patients. Fibrates usually are the drugs of choice for treating severe hypertriglyceridemia and the chylomicronemia syndrome. While the primary therapy is to remove alcohol and lower dietary fat intake as much as possible, fibrates assist by increasing triglyceride clearance and decreasing hepatic triglyceride synthesis. In patients with chylomicronemia syndrome, fibrate maintenance therapy and a low-fat diet keep triglyceride levels well below 1000 mg/dL and thus prevent episodes of pancreatitis.

ADME. Fibrates are absorbed rapidly and efficiently (>90%) when given with a meal but less efficiently when taken on an empty stomach. Peak plasma concentrations are attained within 1-4 h. More than 95% of these drugs in plasma are bound to protein, nearly exclusively to albumin. The t1/2 of fibrates range from 1.1 h (gemfibrozil) to 20 h (fenofibrate). The drugs are widely distributed throughout the body, and concentrations in liver, kidney, and intestine exceed the plasma level. Gemfibrozil is transferred across the placenta. The fibrate drugs are excreted predominantly as glucuronide conjugates (60-90%) in the urine, with smaller amounts appearing in the feces. Excretion of these drugs is impaired in renal failure.

ADVERSE EFFECTS AND DRUG INTERACTIONS. Fibric acid compounds usually are well tolerated. GI side effects occur in up to 5% of patients. Infrequent side effects include rash, urticaria, hair loss, myalgias, fatigue, headache, impotence, and anemia. Minor increases in liver transaminases and alkaline phosphatase have been reported. Clofibrate, bezafibrate, and fenofibrate reportedly potentiate the action of oral anticoagulants, in part by displacing them from binding sites on albumin. Careful monitoring of the prothrombin time and reduction in dosage of the anticoagulant may be appropriate.

A myopathy syndrome occasionally occurs in subjects taking clofibrate, gemfibrozil, or fenofibrate and may occur in up to 5% of patients treated with a combination of gemfibrozil and higher doses of statins. Statin doses should be reduced when combination therapy is employed. Gemfibrozil inhibits hepatic uptake of statins by OATP1B1, and competes for the same glucuronosyl transferases that metabolize most statins. Thus, levels of both drugs may be elevated when they are coadministered. Patients taking this combination should be followed at 3-month intervals with careful history and determination of CK values until a stable pattern is established. Patients taking fibrates with rosuvastatin should be followed especially closely even if low doses (5-10 mg) of rosuvastatin are employed. Fenofibrate is glucuronidated by enzymes that are not involved in statin glucuronidation; thus, fenofibrate-statin combinations are less likely to cause myopathy than combination therapy with gemfibrozil and statins.

All of the fibrates increase the lithogenicity of bile. Clofibrate use has been associated with increased risk of gallstone formation. Renal failure is a relative contraindication to the use of fibric acid agents, as is hepatic dysfunction. Fibrates should not be used by children or pregnant women.

THERAPEUTIC USE. Clofibrate is available for oral administration and may be useful in patients who do not tolerate gemfibrozil or fenofibrate. The usual dose is 2 g/day in divided doses. Gemfibrozil (LOPID) usually is administered as a 600-mg dose taken twice daily, 30 min before the morning and evening meals. The TRICOR brand of fenofibrate is available in tablets of 48 and 145 mg. The usual daily dose is 145 mg. Generic fenofibrate (LOFIBRA) is available in capsules containing 67, 134, and 200 mg. The choline salt of fenofibric acid (TRILIPIX) is available in capsules of 135 and 45 mg. TRILIPIX, 135 mg, is equivalent to TRICOR, 145 mg, and LOFIBRA, 200 mg. Fibrates are the drugs of choice for treating hyperlipidemic subjects with type III hyperlipoproteinemia as well as subjects with severe hypertriglyceridemia (triglycerides >1000 mg/dL) who are at risk for pancreatitis. Fibrates appear to have an important role in subjects with high triglycerides and low HDL-C levels associated with the metabolic syndrome or type 2 diabetes mellitus. In these patients, the LDL levels need to be monitored; if LDL levels rise, the addition of a low dose of a statin may be needed. Many experts now treat such patients first with a statin and then add a fibrate, based on the reported benefit of gemfibrozil therapy.


Ezetimibe is the first compound approved for lowering total and LDL-C levels that inhibits cholesterol absorption by enterocytes in the small intestine. It lowers LDL-C levels by ~20% and is used primarily as adjunctive therapy with statins.

MECHANISM OF ACTION. Ezetimibe inhibits luminal cholesterol uptake by jejunal enterocytes, by inhibiting the transport protein NPC1L1. In human subjects, ezetimibe reduces cholesterol absorption by 54%, precipitating a compensatory increase in cholesterol synthesis that can be inhibited with a cholesterol synthesis inhibitor (e.g., a statin). The consequence of inhibiting intestinal cholesterol absorption is a reduction in the incorporation of cholesterol into chylomicrons; this diminishes the delivery of cholesterol to the liver by chylomicron remnants. The diminished remnant cholesterol content may decrease atherogenesis directly, as chylomicron remnants are very atherogenic lipoproteins. Reduced delivery of intestinal cholesterol to the liver by chylomicron remnants stimulates expression of the hepatic genes regulating LDL receptor expression and cholesterol biosynthesis. The greater expression of hepatic LDL receptors enhances LDL-C clearance from the plasma. Ezetimibe reduces LDL-C levels by 15-20%.

ADME. Ezetimibe is highly water insoluble, precluding studies of its bioavailability. After ingestion, it is glucuronidated in the intestinal epithelium and absorbed and then enters an enterohepatic recirculation. Pharmacokinetic studies indicate that about 70% is excreted in the feces and about 10% in the urine (as a glucuronide conjugate). Bile-acid sequestrants inhibit absorption of ezetimibe, and the 2 agents should not be administered together.

ADVERSE EFFECTS AND DRUG INTERACTIONS. Other than rare allergic reactions, specific adverse effects have not been observed in patients taking ezetimibe. Since all statins are contraindicated in pregnant and nursing women, combination products containing ezetimibe and a statin should not be used by women in childbearing years in the absence of contraception.

THERAPEUTIC USE. Ezetimibe (ZETIA) is available as a 10-mg tablet that may be taken at any time during the day, with or without food. Ezetimibe may be taken with any medication other than bile-acid sequestrants, which inhibit its absorption.

The role of ezetimibe as monotherapy of patients with elevated LDL-C levels is limited to the small group of statin-intolerant patients. The actions of are complementary to those of statins. Dual therapy with these 2 classes of drugs prevents both the enhanced cholesterol synthesis induced by ezetimibe and the increase in cholesterol absorption induced by statins, providing additive reductions in LDL-C levels. A combination tablet containing ezetimibe, 10 mg, and various doses of simvastatin (10, 20, 40, and 80 mg) has been approved (VYTORIN). At the highest simvastatin dose (80 mg), plus ezetimibe (10 mg), average LDL-C reduction was 60%.


ICOSAPENT ETHYL. Icosapent ethyl (VASCEPA) is an ethyl ester derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA). EPA reduces VLDL triglycerides and is used as an adjunct to diet for treatment of adult patients with severe hypertriglyceridemia (≥500 mg/dL). Recommended daily oral dose is 4 g/day administered with food. Adverse effects may include arthralgia. Since omega-3-fatty acids may prolong bleeding time, patients taking anticoagulants should be monitored.

LOMITAPIDE. Lomitapide mesylate (JUXTAPID) acts by inhibiting MTP, which is essential for formation of VLDL. Lomitapide is used as an adjunct to diet for lowering LDL-C, total cholesterol, apoB, and non-HDL-C in patients with homozygous familial hypercholesterolemia. The recommended starting oral dose (5 mg/day) is titrated upwards to a maximum dose of 60 mg daily. The drug is metabolized by CYP3A4 and is contraindicated with inhibitors of CYP3A4. Reported adverse effects include diarrhea, vomiting, abdominal pain, and hepatotoxicity. The agent is used under an FDA risk evaluation and mitigation strategy.

MIPOMERSEN SODIUM. Mipomersen (KYNAMRO), an antisense oligonucleotide, inhibits the synthesis of apoB-100. The drug is approved as an addition to lipid-lowering medications and diet for patients with homozygous familial hypercholesterolemia. The recommended dose is 1 mL of 200 mg/mL solution, injected subcutaneously, once a week. Common adverse effects include injection site reactions, flu-like symptoms, headache, and elevation of liver enzymes. The agent is used under an FDA risk evaluation and mitigation strategy.